Central nervous system (CNS) involvement, one of the most devastating clinical manifestations of tuberculosis (TB)
is noted in 5 to 10% of extrapulmonary TB cases, and accounts for approximately 1% of all TB cases. Definitive diagnosis
of tuberculous meningitis (TBM) depends upon the detection of the tubercle bacilli in the CSF. Every patient with
TBM should preferably be evaluated by imaging with contrast enhanced CT either before or within the first 48 hours of
treatment. An extra-neural focus of tuberculosis should be sought clinically and radiologically in all patients with CNS TB as it
may indicate safer and more accessible sites for diagnostic samplings. A minimum of 9 months treatment is warranted,
prompted by the uncertain influences of disease severity, CNS drug penetration, undetected drug resistance and patient compliance.
All patients with TB meningitis may receive adjunctive corticosteroids at presentation regardless of disease severity even
for those with HIV infection. Drug resistance is strongly associated with previous treatment. The key principle of
managing drug-resistant TB is never to add a single drug to a failing regimen. Early ventriculo-peritoneal shunting should be
considered in those with hydrocephalus failing medical management. The single most important determinant of outcome is the
stage of tuberculous meningitis at which treatment has been started.

Central nervous system (CNS) disease caused by Mycobacterium
tuberculosis is highly devastating, and accounts for approximately 1% of all cases
of tuberculosis (TB). It carries a high mortality and
a distressing level of neurological morbidity, and disproportionately afflicts children and
human immunodeficiency virus (HIV) infected
individuals. The purpose of this review is to highlight the
current epidemiological, clinical, diagnostic, and
therapeutic aspects of CNS tuberculosis.

The global epidemiologic burden of TB

World Health Organisation estimates that 9.27
million new cases of TB occurred in 2007
(139/100,000 population), compared with 9.24 million new
cases (140/100,000 population) in 2006 world
over1. India, China, Indonesia, Nigeria, and South Africa rank
first to fifth in the total number of incident cases.
Among the 15 countries with the highest estimated TB incidence rates, 13
are in Africa, a phenomenon linked to the effect of high rates of HIV coinfection
on the natural history of TB2. Incidence rates are
falling world over except in Eastern Europe, where it
is stable and increasing only in African countries with
a low prevalence of HIV1, 3.

Among the 9.27 million incident cases of
TB in 2007, an estimated 1.37 million (14.8%) are
HIV-positive1. [The global number of incident
HIV-positive TB cases is estimated to have peaked in
2005 at 1.39 million. The relative risk of developing
TB in HIV-positive people compared to HIV-negative people (the incidence rate ratio) is 20.6 in
countries with a HIV prevalence greater than 1% in the
general population, about 26.7 where HIV prevalence
range from 0.1% and 1%, and 36.7 in countries with
a prevalence less than 0.1%.4

Prevalence

About 13.7 million prevalent cases were estimated in 2007 (206/100,000 population), a slight
decrease from 13.9 million in 2006. The global prevalence
of TB is estimated to have been declining since
1990. This decline is in marked contrast to the increase
in TB incidence in the 1990s, which can be
explained by a decrease in the average duration of disease
as the fraction of cases treated in the DOTS programs increased and a comparatively short duration of disease among HIV-positive cases specifically
with limited access to antiretroviral therapy (ART).
The duration of TB among HIV-positive patients is relatively short for in people with advanced
HIV infection, the progression to severe tuberculosis
is rapid, with a marked reduction in life
expectancy5.

Infection of the CNS is one of the most
devastating clinical manifestations of tuberculosis. In an
American epidemiological study of extrapulmonary tuberculosis, up to 10% of cases showed
CNS involvement6, while CDC data indicated that
6.3% of extrapulmonary cases (1.3% of total
tuberculosis cases) had CNS TB. [7] In a Taiwan study, 1.5%
of TB deaths between 1997 and 2001 were
attributable to CNS disease, a percentage that had increased
from previous years8.

Risk factors

Risk factors for CNS tuberculosis include age (children> adults)
HIV-coinfection9, malnutrition, recent measles in
children10], alcoholism, malignancies, the use of immunosuppressive agents in adults
and disease prevalence in the
community11,12.

Clinical features

In most patients with tuberculous meningitis there
is a history of vague ill health lasting 28 weeks
prior to the development of meningeal irritation.
These nonspecific symptoms include malaise,
anorexia, fatigue, fever, myalgias, and headache. Adults
with tuberculous meningitis (TBM) can often present
with the classic meningitis symptoms of fever,
headache and stiff neck along with focal neurological
deficits, behavioral changes, and alterations in
consciousness14. A history of tuberculosis is elicited in
only approximately 10% of patients14. The presence
of active pulmonary tuberculosis on chest X- ray
ranges from 30 to 50%. Patients coinfected with HIV
do not seem to have an altered presentation of
TBM15.About 10% of cases with TBM have some
form of spinal tuberculosis. (Table. 1)

Cerebrovascular complications of tuberculous meningitis that occur typically as
multiple or bilateral lesions in the territories of the
middle cerebral artery perforating vessels are termed
as tuberculous vasculopathy. Vessel pathology
appears to be a consequence of its immersion in the
local inflammatory exudate. Infiltrative, proliferative
and necrotising vessel pathologies have been
described, leading to luminal thrombosis. There is
some evidence that vasospasm may mediate strokes
early in the course of the disease and proliferative
intimal disease later strokes16.

Children with TBM often present with
fever, stiff neck, seizures, and abdominal symptoms
such as nausea and vomiting. Headache occurs less
often than in adults. Depending on the stage of presentation, neurological symptoms range
from lethargy and agitation to coma. TBM in
children develops most often within 3 months of
primary tuberculosis infection17. A family history
of tuberculosis can be identified in approximately
50 to 60% of children, and a positive tuberculin
skin test is found in approximately 30 to 50%. 16 In children particularly, there appears to be a
close association with disseminated (miliary)
tuberculosis17. Clinical signs of patients presenting with TBM
can be easily assessed for severity based on
modifications of the Medical Research Council staging
system, which has been shown to have considerable prognostic value. A more
contemporary modification of the staging system is given in
table 218.

Cranial nerve palsies occur in 2030% of
patients and may be the presenting manifestation of
TBM. The sixth cranial nerve is most commonly
affected19.

Vision loss due to optic nerve involvement
may occasionally be a dominant presenting illness. Optochiasmatic arachnoiditis,
third ventricular compression of optic chiasma (if
hydrocephalus develops), optic nerve granuloma are
possible factors for vision loss in these
patients. Ophthalmoscopic examination may reveal papilloedema. Funduscopy may
reveal choroid tubercles, yellow lesions with indistinct borders present either
singly or in clusters. These
choroid tubercles are more frequent with
tuberculous meningitis associated with miliary tuberculosis
and are virtually pathognomonic (table 3), although
they are present in only 10% of patients in whom
the meningitis is not associated with miliary
involvement20.

Clinical manifestations of tuberculoma or
tuberculous brain abscess depend largely on their location,
and patients often present with headache,
seizures, papilledema, or other signs of increased
intracranial pressure. The presentation of brain abscess is
more sub acute (1 week to 3 months) than
tuberculoma but slower in onset than pyogenic brain
abscesses21. See Table 4 for comparison of the presenting
clinical variables independently predictive of
tuberculous meningitis in various published studies.

Tuberculous Encephalopathy (TBE)

TBE is a rare outcome usually more common
in younger population and is characterized by
diffuse brain edema and demyelination, which usually
is extensive27. Microscopically it is characterized
by microvascular necrosis with perivascular
macrophage reaction and demyelination along with focal
glial nodules in the white matter and occasional hemorrhagic lesions. Impaired
consciousness, seizures, disseminated intravascular coagulation, signs and
symptoms of meningitis with or without
spinal fluid changes characterize this syndrome.
This syndrome may be one of the leading causes of neurologic devastation and
death in CNS TB
patients with high alcohol intake.

Spinal tuberculosis

Involvement of the spine occurs in less than 1%
of TB patients and it can be secondary to Pott's
spine or as non-osseous spinal cord tuberculosis or
spinal tuberculous meningitis. It is a leading cause
of paraplegia in developing nations. In Pott's
spine infection in the vertebral bodies usually starts
in cancellous bone adjacent to an intervertebral disc
or anteriorly under the periosteum of the
vertebral body; the neural arch is rarely affected.
Vertebral destruction leads to collapse of the body of
the vertebra along with anterior wedging. Spinal
cord compression in Pott's spine is mainly caused
by pressure from a paraspinal abscess.
Neurological deficits may also result from dural invasion
by granulation tissue and compression from the
debris of sequestrated bone, a destroyed intervertebral
disc, or a dislocated vertebra. Rarely, vascular
insufficiency in the territory of the anterior spinal artery has
also been suggested. Neurological involvement can
occur at any stage of Pott's spine and even years later,
when there hasbeen apparent healing, because of
stretching of the cord in the deformed spinal canal.
The thoracic spine is involved in about 65% of
cases, and the lumbar, cervical and thoracolumbar
spine in about 20%, 10% and 5%, respectively. The
atlanto-axial region may also be involved in less than 1%
of cases. Males are affected more often than females
in most series, and the disease generally affects
young persons.

Typically, there is a history of local
pain, tenderness over the affected spine or even
overlying bony deformity in the form of gibbus.
Paravertebral abscess may bepalpated on the back of a
number of patients. These patients usually have acute
or subacute, progressive, spastic type of
sensorimotor paraparesis. The incidence of paraparesis in
patients with Pott's spine varies from 27% to
47%.28

Non-osseous spinal cord tuberculosis
can occur in the form of tuberculomas. Dastur 29 reviewed 74 cases of tuberculous paraplegia
without evidence of Pott's disease and observed
that extradural tuberculomas occurred in 64% while arachnoid
lesionswithout dural involvement, and subdural/extramedullary lesions occured in 8%
of patients in each group. Intramedullary
tuberculomas are extremely rarely reported and are
frequently located in the thoracic region. More than one site
in the spinal cord may also be affected. The
clinical features are indistinguishable from those of
any extramedullary or intramedullary tumour,
although acute worsening may occur. Non-osseous spinal cord tuberculomas may increase in size while the
patient is on antituberculous therapy.

A predominantly spinal form of
tuberculous meningitis may result from rupture of Rich's
focus into the spinal arachnoid space rather than the
basal meninges. The acute form presents with
fever, headache, and radiating root pains,
accompaniedby myelopathy. The chronic form, usually localised to
a few segments, presents with progressive spinal
cord compression and may suggest a spinal cord
tumour. The characteristic MRI features include CSF
loculation and obliteration of the spinal subarachnoid
space with loss of outline of spinal cord in the
cervico-thoracic region and matting of nerve roots in
the lumbar region. Spinal forms of tuberculous meningitis may be associated with syrinx
formation29.

Immune Reconstitution
Inflammatory Syndrome and TB

Two forms of Immune
Reconstitution Inflammatory Syndrome (IRIS) are recognized
in the case of TB. (a) Paradoxical TB-IRIS occurs
in patients diagnosed with TB and established on
TB treatment before ART, who then manifest with recurrent or new TB symptoms and
clinical manifestations after ART initiation.(b)
Unmasking TB-IRIS occurs in patients who are not on
TB treatment when they start ART, and who then
have an unusually inflammatory presentation of TB in
the first 3 months of ART 30.

Paradoxical TB-IRIS reactions during
TB treatment (new or recurrent TB symptoms, or
signs occurring after initial response to treatment)
occur in patients not infected with HIV-1 and
patients infected with HIV-1 and not on ART.
Manifestations include recurrent fevers, worsening
pulmonary infiltrates, enlarging pleural effusions,
the development of TBM, new or enlarging tuberculomas, or tuberculous lesions
developing at other anatomic sites. The pathogenesis has
variably been attributed to a combination of the
following factors: release of new antigen targets
during mycobacterial killing, hypersensitivity to
such antigens, and exaggerated immune restoration (following TB-induced
immunosuppression) occurring on TB treatment. The development
of paradoxical reactions in patients not infected
with HIV-1 is associated with greater increases in
total lymphocyte count on TB treatment.
Paradoxical reactions are also far more frequent in the
period after ART initiation than in patients not infected with HIV-1 and patientsinfected
with HIV-1 and not on ART (36% vs 2% vs 7%, respectively, in one
study31.The risk factors for paradoxical IRIS
are disseminated TB, low CD4 count before ART, and shorter interval from TB
treatment to ART.It is important to investigate for other
opportunistic infections and malignancies, TB treatment failure
(due to nonadherence, TB drug resistance, or malabsorption of TB drugs), or
drug reaction. In addition, TB-IRIS may develop in patients with undiagnosed
rifampicin resistance,
clinically indistinguishable from TB-IRIS which occurs
in patients with drug-susceptible disease. If
possible, drug susceptibility testing, preferably a
rapid diagnostic assay, should be performed in all
patients presenting with paradoxical TB-IRIS. Corticosteroids have been used
for management of TB-IRIS when alternative diagnoses have been excluded. Unmasking
TB-IRIS is less
well characterized than paradoxical TB-IRIS, with
fewer cases reported. A subset of these cases
presenting with heightened intensity of clinical
manifestations, particularly when there is evidence of a
marked inflammatory component, during the first 3
months of ART are termed as ``unmasking TB-IRIS.''

Diagnosis

Investigations

Definitive diagnosis of tuberculous meningitis depends upon the detection of the tubercle
bacilli in the CSF, either by smear examination or
by bacterial culture. Standard staining techniques
using such stains as Ziehl-Neelsen, Kinyoun, or
auramine-rhodamine applied to CSF samples have
been estimated to detect approximately 100 AFB/ml
of CSF. It has been claimed that if large volumes
of CSF are carefully examined the organism can be found in over 90% of centrifuged CSF
specimens (Table 5), the highest detection rates being
achieved in ventricular fluid.

Rates of CSF culture positivity for
clinically diagnosed cases range from 25% to 70%.
The importance of obtaining a culture is that growth
of MTB in culture allows drug sensitivity testing,
which can have a large impact on appropriate drug
selection and prognosis.

At any age, approximately 10% of total
CSF volume can be taken for examination.

MTB has been isolated from significantly smaller
CSF volumes from HIV infected than in uninfected
individuals29. Once anti-tuberculosis medication
is commenced, the sensitivity of smear and culture
falls rapidly. The deposit should be stained and
cultured on solid or in liquid media .An aliquot of
deposit may be taken for nucleic acid amplification
if required. Liquid culture media may recover more bacteria from CSF than solid
media32. A tissue biopsy has much higher diagnostic yield than CSF for
the diagnosis of tuberculoma and spinal tuberculosis.
A careful search should be made for extra-neural disease that may be biopsied safely. Gastric
aspirates and bone marrow aspirates may assist in
detecting extra-neural tuberculosis in children. Stereotactic
brain biopsy confirms the diagnosis of abscesses
and atypical tuberculomas when others diagnostic
tools fail.

Molecular and Biochemical Analysis

Currently available molecularly based techniques, include commercially available nucleic
acid amplification (NAA) methods and other
polymerase chain reaction (PCR) based methods,
antibody detection, antigen detection, or chemical assays
such as adenosine deaminase (ADA) and
tuberculostearic acid measurements.

PCR technique

Commercial nucleic acid amplification (NAA)
assays for the diagnosis of TBM are 56 percent
sensitive and 98 percent specific and the diagnostic yield of NAA increases
when large volumes of CSF are processed33. The sensitivity of microscopy is
similar to NAA for the diagnosis of
TBM34. The sensitivity of CSF microscopy and culture falls rapidly
after the start of treatment, whereas mycobacterial
DNA may remain detectable within the CSF until one month after the start of treatment. NAA (e.g.
PCR) may be performed on CSF for all forms of CNS
tuberculosis35, 36. NAA assays that detect
the rifampicin resistance genotype should be
requested when the risk of drug resistant tuberculosis is high.

Tuberculin skin test
(TST)

The diagnostic utility of skin testing being
positive for CNS tuberculosis varies from
10-20%37 to 50%. 38 The performance of the tuberculin skin test
for the diagnosis of tuberculosis varies according to
age, vaccination with BCG, nutritional status, HIV infection, and technique of
administration39. TST like interferon-gamma release assays may
provide indication of previous tuberculosis infection;
neither is sufficiently sensitive nor specific to diagnose
active disease40.

Interferon- y release assays (IGRAs): A major advance in recent times has been the
development of T-cell-based interferon- y release assays
(IGRAs). IGRAs are in vitro tests that are based on
interferon- y (IFN- y) release after T-cell stimulation by
antigens (such as early secreted antigenic target 6
[ESAT6] and culture filtrate protein 10 [CFP10]) that are
more specific to MTB than the purified protein
derivative (PPD). Two IGRAs are currently available
as commercial kits. Systematic reviews have
reported strong evidence that IGRAs have high specificity
that is unaffected by bacille Calmette-
Guérin(BCG) vaccination41,
42. [TST, in contrast, has high
specificity in populations who have not been vaccinated
with BCG but specificity is modest and inconsistent
in populations vaccinated with BCG. The high specificity of IGRAs is proving to be useful
in individuals vaccinated with
BCG43. [IGRAs may be excellent options in these populations and it
seems to be at least as sensitive as
TST42. Both these immune-based tests merely indicate a cellular
immune response to recent or remote sensitization with
MTB. IFN-y can be easily induced in peripheral
blood monocytes or whole blood through antigenic stimulation in sufficient quantities that it can
be detected using simple technologies, such as
ELISA. IGRA tests rely on detecting elevated
IFN-y production after stimulation with antigens
(ESAT- 6, CFP10). Because these antigens are largely
restricted to members of the MTB complex, the tests are
not confounded by BCG or environmental mycobacteria. Because IGRAs cannot
distinguish between latent and active TB, a positive IGRA
result may not necessarily indicate active TB. A
negative IGRA result would not conclusively rule out
active disease in an individual suspected to have TB
(similar to the results of a TST). About 50% of
patients with culture-confirmed TBM had no
detectable MTB -specific interferon-gamma
producing lymphocytes in peripheral blood at
presentation40.

The use of IGRAs is steadily increasing
in countries with low or intermediate incidence.
Despite the large number of publications on IGRAs, evidence is still limited on the prognostic value
of these tests, and their added value in TB
diagnosis44.There is growing evidence that the performance
of IGRAs varies between countries with high and
low incidence of TB45.Their role, if any, seems to
be limited in low income countries with a high TB burden.

ADA

ADA is associated largely with
lymphocytic proliferation and differentiation and is
considered to be a marker of cell-mediated
immunity46. The measured sensitivities and specificities of ADA
in the CSF range from 44 to 100% and 71 to 100%,
respectively47. In one study, ADA was not
valuable in distinguishing TBM in patients with HIV
infection. [48] Standardized cutoffs of ADA values for
the diagnosis of TBM have not been established,
and the values used in various studies ranged from
>5.0 to >15 IU/liter. CSF ADA measurements have
been found to be useful in predicting poor
neurological outcomes among pediatric TBM
cases49. Raised ADA activity in the CSF of patients with CNS TB
lacks specificity. High CSF ADA activity has been
reported from patients with lymphomas, malaria,
brucellosis, pyogenic meningitis, cryptococcal meningitis,
and cerebral lymphomas50, 51. CSF ADA activity is
not recommended as a routine diagnostic test for
CNS tuberculosis35.

Tuberculostearic acid

Tuberculostearic acid is a fatty acid component
of the M. tuberculosis cell wall52. Although its
estimation has good sensitivity and specificity in limited
studies, the requirement for expensive equipment has
limited its clinical use.

Radiological Evaluation

Every patient with TBM should preferably
be evaluated with contrast enhanced CT imaging
before the start or within the first 48 hours of
treatment35.Early brain CT can help diagnose TBM, and
will provide important baseline information
regarding surgical interventions for hydrocephalus.
Choroid plexus enhancement with ventricular enlargement
on imaging is highly suggestive of TBM. In TBM,
MRI shows diffuse, thick, meningeal enhancement. Cerebral infarcts can be seen in nearly 30% of
cases53. A study from South Africa reported that
the combination of hydrocephalus, basal
enhancement and infarction was 100% specific and 41%
sensitive for the diagnosis of childhood TBM, although
the authors suggested pre-contrast hyperdensity in
the basal cisterns as the best predictor of
TBM54.

Contrast enhanced MRI is
generally considered as the modality of choice. It is
useful for assessment of the location of lesions and
their margins, as well as ventriculitis, meningitis and
spinal involvement (sensitivity 86%, specificity
90%)55.A large lipid, lactate peak has been used to
specifically identify tuberculomas by magnetic
resonance spectroscopy56. All patients should have a
chest-X-ray as part of the diagnostic
assessment35.Serial transcranial doppler ultrasonography (TCD)
with blood flow velocity (Vm) and pulsatility index
(PI) measurments, can be efficiently utilized to prognosticate outcome in tuberculous
meningitis-related vasculopathy. In early phase I
vasculopathy TCD reveals increased Vm and normal to
moderately decreased PI and these patients have
reversible ischemic deficits while late phase III is
characterized by almost absent blood flow in one or more
basal arteries and, accordingly, by associated brain
tissue infarction and permanent severe neurological
deficit or fatal outcome57.

Treatmentof CNS TB

The first combination therapy for TB consisted
of para-aminosalicylic acid (PAS) and isoniazid (H)
in addition to streptomycin, given for 24 months,
and it became the basis for treatment of TB in the developed world for about
a decade. In the mid 1960s, PAS was replaced by ethambutol (E), a
better-tolerated drug, and the treatment duration
was reduced from 24 to 18 months. In the late
1960s rifampicin-containing regimen including
isoniazid, ethambutol, and streptomycin offered a
predictable cure in more than 95% of patients with 9- to
12-month duration of therapy. In the early 1980s addition of pyrazinamide (Z)
in the intensive phase of treatment, decreased the duration of a fully
orally administered treatment to 6 to 8 months.
Studies conducted in East Africa showed that the
relapse rate after a 6-month regimen was reduced from
22% to 8% by the addition of pyrazinamide, and to
3% by the addition of rifampicin58.

Since the 1980s the 6- to 8-month regimen, using a 4-drug combination (HRZE) in the
initial phase followed by a 2-drug combination (HR
or HE) in the continuation phase, has been widely
accepted59.In 2004 the results of a
multicenter randomized clinical trial, showed higher efficacy
for the 6-month regimen (2 months of HRZE plus 4 months of HR: 2HRZE/4HR) compared with
the 8-month therapy (2HRZE/6HE)60. The recommended first-line treatment agents for
all forms of CNS tuberculosis are Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
taken daily either individually or in combination form
(table 6).

Patients should be treated for a minimum of
10 months35.Therapy should be extended to at least
12 months in those who fail to respond, or if
treatment interruptions have occurred for any reason.
Isoniazid penetrates the CSF freely61 and has potent
early bactericidal activity. At standard doses
isoniazid achieves CSF levels 10-15 times the
minimum inhibitory concentration of M.
tuberculosis62. The main disadvantage of INH is that resistance
develops quite quickly when used as monotherapy though this
does not seem to happen when it is used to eradicate
the organism in a patient who has become infected
but has not yet developed overt signs or symptoms
of infection (chemoprophylaxis). Pyridoxine is
extremely effective in stopping the seizures, reversing the coma, and correcting
the metabolic acidosis triggered by any acute overdose of isoniazid. Treatment
is best given as a relatively rapid intravenous (IV)
infusion, the standard dose being one mg of pyridoxine
for every mg of isoniazid the patient is thought to
have taken63. Crushed tablets can be given down
a nasogastric tube if no IV preparation is readily available. Prompt treatment is called for
because INH dose in excess of 90 mg/kg is extremely
likely to trigger recurrent seizure activity, which can
be fatal64.Rifampicin penetrates the CSF less
well (maximum concentrations around 30% of
plasma), but the high mortality from rifampicin resistant
TBM has confirmed its key role in the treatment of
CNS disease65. The incidence of ethambutol induced
optic neuritis is less than 3% at the standard dose of
15-20 mg/kg though it is a concern, especially
when treating comatose patients66.Fluoroquinolones are an effective fourth agent (if ethambutol
is contraindicated), but should be avoided in
women who are pregnant or breastfeeding and
prolonged fluoroquinolone therapy is not advised for
children67. Interruptions in treatment are an independent
risk factor for death from TBM68.

Rationale use of steroids in CNS TB

All patients with TBM may receive adjunctive corticosteroids regardless of disease severity
at presentation. Adults (>14 years) should
start treatment with dexamethasone 0.4 mg/kg/24
hours with a tapering course over 6 to 8 weeks.
Children (d"14 years) should be given prednisolone
4mg/kg/24 hrs (or equivalent dose dexamethasone:
0.6 mg/kg/24 hrs) for 4 weeks, followed by a
tapering course over 4 weeks69.The role of routine adjunctive corticosteroids for all patients with
tuberculomas without meningitis, or with spinal cord
tuberculosis is arguable albeit corticosteroids may be helpful
in those patients whose symptoms are not
controlled, or are worsening, on anti-tuberculosis therapy.
Doses similar to those used for TBM should be
given. Thalidomide may be helpful in patients with tuberculomas that are not responding to
anti-tuberculosis drugs and high dose
corticosteroids70.

Management of CNS TB in HIV infected

CNS tuberculosis in HIV infected patients
should be managed with the same anti-tuberculosis
drug regimen as that recommended for HIV
uninfected individuals; whenever possible the regimen
should include rifampicin. Adjunctive corticosteroids
are recommended for those with TBM and HIV infection. Starting anti-retroviral
therapy depends upon balancing the risks of drug interactions
and Immune Reconstitution Inflammatory Syndrome (IRIS) when started early and
opportunistic
diseases if delayed. If CD4 > 200 cells/ìl it is better to
defer HIV treatment as long as possible, ideally until
end of tuberculosis treatment35.Start anti-retroviral
treatment (ART) if the CD4 count falls below
200 cells/ìl during tuberculosis treatment. If CD4 is
100-200 cells/ìL start ART after approximately 2
months of anti-tuberculosis treatment so that risk of IRIS
is minimised. If CD4 is < 100 cells/ìL start ART
within the first 2 weeks of anti-tuberculosis
treatment. Rifampicin will induce the metabolism of
protease inhibitors, delavirdine and nevirapine reducing
the level of these drugs. When possible, treat
with rifampicin and a non-nucleoside reverse
transcriptase inhibitor (NNRTI), preferably efavirenz but the
dose of efavirenz should be increased to 800mg. Rifabutin should be used if treatment
with a protease inhibitor (PI) is required, but at a reduced
dose (usually 150mg 3 times per week). If efavirenz
and rifabutin are co-administered, a 450 mg daily
dosage of rifabutin is recommended.

Management of common
treatment complications, including drug-induced hepatitis

New or worsening neurological signs in patients
on treatment for CNS tuberculosis should prompt immediate imaging. Hyponatraemia should
be considered as a cause of coma and seizures.
Slow correction of sodium either by sodium and
water replacement if the patient is hypovolaemic, or
by fluid restriction if they are euvoleamic is advised
to prevent risk of myelinolysis.

If drug-induced hepatitis occurs, and if
serum transaminases rise above five times normal
stopping pyrazinamide, continuing isoniazid,
rifampicin, ethambutol, and performing daily liver function
tests is recommended35. If serum albumin falls,
the prothrombin time rises, or the transaminases
continue to rise, isoniazid and rifampicin should be
withdrawn. Streptomycin and ethambutol should be given,
along with moxifloxacin or levofloxacin. Rifampicin
and isoniazid should be restarted once the liver
function tests are normal (table 7).

In a recent study 175 patients with a diagnosis of antituberculosis drug-induced hepatotoxicity
(DIH) were randomized to receive 1 of 3 different predefined reintroduction regimens in which
one group were given isoniazid, rifampicin, and pyrazinamide simultaneously at full dosage from
day 1 while the other received antituberculosis drugs in
a manner similar to that recommended in the American Thoracic Society guidelines
for reintroduction and the third were administered
drugs accordance with British Thoracic Society
guidelines71.19 patients (10.9%) had recurrence of DIH
during follow-up and the recurrence rate was not significantly different between the 3
groups. Pretreatment serum albumin level was the
only statistically significant predictor of future
recurrence of DIH on reintroduction of antituberculosis
drugs. Patients with life-threatening tuberculosis can
be reintroduced simultaneously at full dosage
safely from day 1 with all 3 of the potentially
hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide).

Role of neurosurgery

Hydrocephalus, tuberculous brain abscess (TBA), and vertebral tuberculosis with
cord compression are all indications for urgent neurosurgical
referral though early hydrocephalus and tuberculous
brain abscess can be successfully treated by drugs alone
. So early recognition and timely treatment is
critical in avoiding the surgery.TBA occurs in only 4%
to 8% of patients with CNS TB who do not have HIV infection but in 20% of patients
who do have HIV infection. The aim of surgical management of
TBA is to reduce the size of the space-occupying
lesion and thereby diminish intracranial pressure and
to eradicate the pathogen. Early surgical drainage
and chemotherapy are considered the most
appropriate treatment for TBA and can be therapeutic as well as diagnostic.
It should be carefully planned and individualized according to the patient's
clinical condition, anatomic localization, and the number
of lesions. Early anti tuberculous therapy (ATT)
must be considered in all cases of suspectedTBA even before surgery,
in order to reduce the risk of postoperative meningitis. An open surgical
excision is an appropriate treatment option for
large, multiloculated cerebellar lesions that cause
brain herniation and also in those that do not respond
to aspiration while stereotactic-guided aspiration
is preferred in eloquent or deep-seated areas such
as the hypothalamus, thalamus, or deep temporal regions in order to prevent severe
neurological sequelae. The main disadvantage of the latter
option is the need forrepeated procedures in as many
as 70% of patients, and the high risk of rupture
into ventricles or the subarachnoid space, which
could lead to ventricular ependymitis or meningitis
and worsening of neurological deficits. An early
surgical procedure can improve the efficacy of
ATT, promote a better clinical response after
reduction of bacillary load and reduce
mortality72.Hydrocephalus, either
communicating(more common) or obstructive, is one of the
commonest complications of TBM occurring in up to 85%
of children with the disease in whom it is more
severe than in adults. Patients with TBM and
hydrocephalus who have a Glascow coma scale (GCS) of 15
(with or without focal neurological deficit) could be
tried for a few days or a week on diuretics and
steroids with close monitoring to detect any worsening
or lack of improvement and a shunt should promptly be offered in case of failure
of medical management. Ventriculoperitoneal shunt is the procedure of
choice if the duration of illness is <4 weeks
while endoscopic third ventriculostomy or ventriculoperitoneal
shuntcan be offered if duration >4weeks. Patients with GCS >8 and <14
are better off with an early shunt procedure and so are those with GCS >3
and <8 who improve within 48 hours after an external ventricular drainage
(EDV) while those with GCS >3 and <8 who fail the EDV trial are unlikely
to benefit with shunt and are managed conservatively73.Urgent
surgical decompression should be considered in all those with extradural lesions
causing paraparesis74.

Prognosis and sequelae

The single most important determinant of outcome, for both survival and sequelae, is the stage
of tuberculous meningitis at which treatment has
been started others being extremes of age,
malnutrition, hydrocephalus, focal neurological deficit
,presence of miliary disease , underlying debilitating
disease and alcoholism. If treatment is started in stage
I, mortality and morbidity is very low, while in
stage III almost 50% of patients die, and those
who recover may have some form of neurological
deficit75. Survivors manifest a variety of
neurological sequelae. Intracranial calcification develops in
20% to 48% of patients with tuberculous
meningitis, usually becoming detectable 2 to 3 years after
the onset of the disease76.

Conclusion

Early recognition and timely treatment of CNS TB is critical if the considerable mortality and
morbidity associated with the condition is to be prevented.
A minimum of 10 month-treatment is warranted, and the single most important determinant of
outcome is the stage of tuberculous meningitis at
which treatment has been started.